The research is designed to determine: a) the mechanism of beta-hydroxybutyrate (beta HB) transport in cell plasma membranes and in the blood-brain barrier, b) the mechanism by which beta HB permeability of the blood-brain barrier is enhanced in ketotic states, and c) the biological significance of this modulation. Effects of pH on equilibrium exchange of beta HB in erythrocytes showed that acidification increased both the exchange Vmax and exchange Km. This is not expected of a beta HB negative/OH negative antiport mechanism; but is explained by a beta HB negative/H positive symport mechanism, where an immobile, unprotonated beta HB-carrier complex is postulated. The monocarboxylate carrier of erythrocytes will be solubilized and reconstituted in liposomes in hopes of purifying and characterizing the carrier. Information on the basic mechanism of beta HB transport in erythrocytes and thymocytes will be used to help determine the mechanism of cerebral beta HB-transport modulation. The intra-carotid injection technique will be used to measure cerebral beta HB transport in normal and fat-fed rats, and alterations of the injectant solution will be used to test hypotheses concerning the transport mechanism and the mechanism of its modulation. The effects of capillary-to-brain beta HB transport on the brain:serum distribution of other permeants will be examined to determine the transport partner(s) of beta HB. The effects of the modulation on cerebral beta HB utilization and glucose utilization will be examined.